The overall objective of this multidisciplinary research program is to investigate fundamental mechanisms of the tendon injury and repair process due to overuse injury, and to relate specific resulting biological processes to biomechanical properties. The rotator cuff tendons are used as a paradigm for overuse injuries in tendons in general. The large majority of current knowledge on these processes is derived from clinical studies in human patients. While important, these studies were not designed to test hypotheses related to mechanistic and quantitative study of the properties of the tendons themselves, nor were they focused at the early stages of disease. This deficiency is due to the fact that, in the early stages of the human condition, only global measures such as arm strength can be obtained and, only at the end stage of disease at the time of surgery, can tissue biopsies be ethically obtained for cellular or tissue level analysis. Through human studies, the cellular mechanism of the injury process, whether the tendons heal, and to what extent they return to their normal properties are not known. Without this information, it is not possible to understand the underlying mechanisms of the injury process or to develop targeted prophylactic or therapeutic treatment protocols. Over the past grant period, our research group has identified and utilized an animal model appropriate for studying a variety of rotator cuff tendon injury mechanisms including overuse. This model produces an injury consistent with the available data at later time points from the human condition. With a reliable and established model now in place, the multidisciplinary studies proposed in the current continuing program are possible. Our global hypothesis is that the predominant injury process of altered mechanical loading induces altered cytokines and gene expression driving a dramatic, continual increase in extracellular matrix ECM molecules of altered variety and organization (fibrotic response) resulting in specific deficiencies in biomechanical properties of the tendon tissue. We will rigorously evaluate our resulting specific testable hypothesis via biomechanical, histologic, biochemical, and molecular biologic assays of rotator cuff tendons.